This invention relates to fused imidazole derivatives having multidrug resistance modulating properties, and their use for improving oral bioavailability of pharmaceutical agents that are poorly absorbed from the gastrointestinal tract.
Many valuable pharmaceutical agents cannot be effectively administered by the oral route because of poor systemic absorption from the gastrointestinal tract. All these pharmaceutical agents are, therefore, generally administered via intravenous or intramuscular routes, requiring intervention by a physician or other health care professional, entailing considerable discomfort and potential local trauma to the patient and even requiring administration in a hospital setting with surgical access in the case of certain iv infusions.
It has been suggested that, in some cases, the poor bioavailability of pharmaceutical agents after oral administration is a result of the activity of a cell surface protein P-glycoprotein P-gp, which acts as an energy-dependent transport or efflux pump to decrease intracellular accumulation of said agent by extruding it from the cell. This P-glycoprotein has been identified in secretory epithelial cells of the liver, pancreas, small intestine, colon, and kidney; endothelial capillary cells of the brain and testis, placental trophoblasts; and the adrenal gland.
It is believed that the P-glycoprotein efflux pump prevents certain pharmaceutical compounds from transversing the mucosal cells of the small intestine and, therefore, from being absorbed into the systemic circulation.
Furthermore, it is believed that a major cause of multidrug resistance (MDR) is overexpression of the mdr-1 gene which codes for the expression of P-glycoprotein. P-glycoprotein decreases the intracellular concentration of cytotoxic drugs by binding the drug and actively pumping it out of the cell before it reaches a critical cytotoxic concentration (Dalton W. S., Seminars in oncology, 20:66-69, 1993). The term multidrug resistance (MDR) describes the phenomenon by which cells, in particular cancer cells, become resistant to multiple drugs that may have little similarity in the structure or mechanism of action.
Therefore, it has been suggested that compounds that are able to decrease, avoid, eliminate, inhibit or reverse the effects of multidrug resistance (i.e. so-called MDR reversing agents or compounds having MDR reversing properties) exert their action by blocking, inhibiting or suppressing the function of the P-glycoprotein efflux pump.
Since it is believed that the presence of P-glycoprotein in the gut epithelium can limit the uptake of certain orally administered pharmaceutical agents from the intestine, it is suggested that MDR inhibitors would be very useful to improve the bioavailability of orally administered pharmaceutical agents which are themselves poorly absorbed or not absorbed at all from the gastrointestinal tract.
EP-0,518,435 and EP-0,518,434, published on Dec. 16 1992, disclose fused imidazole compounds having antiallergic activity. WO-94/13680 published Jun. 23, 1994, discloses substituted imidazo[1,2-a](pyrrolo, thieno and furano) [2,3-d]azepine derivatives having antiallergic activity. Also WO-95/02600, published on Jan. 26 1995, discloses other piperidinyl- or piperidinylidene substituted imidazoazepine derivatives having antiallergic activity.
WO-93/16044, published on Aug. 19, 1993, discloses triphenyl-azacycloalkane derivatives effective in reversing drug resistance in multi-drug resistant tumors. WO-94/22842, published on Oct. 13, 1994, encompasses 1-amino-3-phenoxy propane derivatives as modulators of multi-drug resistance.
WO-97/34897, published on Sep. 25, 1997, discloses the fused imidazole derivatives of formula (I) as multidrug resistance modulators.
The compounds of the present invention differ from the cited art-known compounds structurally, by the nature of the substituents on the nitrogen of the piperidine moiety, and pharmacologically by the fact that, unexpectedly, these compounds have MDR modulating properties.
The present invention relates to the use of a first pharmaceutical compound of formula (I) for the manufacture of a medicine to improve the oral bioavailability of a second pharmaceutical agent that is poorly absorbed or not absorbed at all from the gastrointestinal tract or gut by pre-administering and/or simultaneously co-administering a first pharmaceutical compound of formula (I) to a warm-blooded animal by the oral route.
The phrases xe2x80x9coral bioavailabilityxe2x80x9d and xe2x80x9cbioavailability upon oral co-administrationxe2x80x9d as used herein refer to the systemic availability (i.e. blood/plasma levels) of a given amount of a pharmaceutical agent administered orally to a warm-blooded animal, in particular a human.
This invention concerns the use of a first pharmaceutical compound of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
n is 1 or 2;
R1 is hydrogen; halo; formyl; C1-4alkyl; C1-4alkyl substituted with 1 or 2 substituents each independently selected from hydroxy, C1-4alkyloxy, C1-4alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula
xe2x80x94Xxe2x80x94COxe2x80x94OR5xe2x80x83xe2x80x83(a-1);
xe2x80x94Xxe2x80x94COxe2x80x94NR6R7xe2x80x83xe2x80x83(a-2); 
or
xe2x80x94Xxe2x80x94COxe2x80x94R10xe2x80x83xe2x80x83(a-3);
xe2x80x83wherein
xe2x80x94Xxe2x80x94is a direct bond, C1-4alkanediyl or C2-6alkenediyl;
R5 is hydrogen; C1-12alkyl; Ar; Het; C1-6alkyl substituted with C1-4alkyloxy, C1-4alkyloxycarbonylC1-4alkyloxy, Ar or Het;
R6 and R7 each independently are hydrogen or C1-4alkyl;
R10 is imidazolyl, thiazolyl or oxazolyl;
R2 is hydrogen, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkyloxycarbonyl, carboxyl, formyl or phenyl;
R3 is hydrogen, C1-4alkyl or C1-4alkyloxy;
R4 is hydrogen, halo, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl;
Z is Z1 or Z2;
wherein
Z1 is a bivalent radical of formula xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94or xe2x80x94CHxe2x95x90CHxe2x80x94; provided that when the dotted line is a bond, then Z1 is other than xe2x80x94CH2xe2x80x94;
Z2 is a bivalent radical of formula xe2x80x94CHOHxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94 or xe2x80x94C(xe2x95x90NOH)xe2x80x94CH2xe2x80x94;
xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula
xe2x80x94Yxe2x80x94CR8xe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-1);
xe2x80x94CHxe2x95x90CR8xe2x80x94Yxe2x80x94xe2x80x83xe2x80x83(c-2);
xe2x80x94CHxe2x95x90CR8xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-3);
xe2x80x94CHxe2x95x90CHxe2x80x94CR8xe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c-4);
or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CR8xe2x80x94xe2x80x83xe2x80x83(c-5);
xe2x80x83wherein
each R8 independently is hydrogen, halo, C1-4alkyl, C1-4alkyloxy, hydroxyC1-4alkyl, hydroxycarbonylC1-4alkyl, formyl, carboxyl, ethenyl substituted with carboxyl, or ethenyl substituted with C1-4alkyloxycarbonyl;
each Y dependently is a bivalent radical of formula xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR9xe2x80x94; wherein R9 is hydrogen, C1-4alkyl or C1-4alkylcarbonyl;
xe2x80x94A1xe2x80x94 is a direct bond; C1-6alkanediyl; C1-6alkanediyl-oxy-C1-6alkanediyl; C1-6alkanediyloxy; carbonyl; C1-6alkanediylcarbonyl; C1-6alkanediyloxy substituted with hydroxy;,or C1-6alkanediyl substituted with hydroxy or xe2x95x90NOH;
A2xe2x80x94 is a direct bond or C1-6alkanediyl;
Q is phenyl; phenyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; naphthalenyl; naphthalenyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; pyridinyl; pyridinyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; quinolinyl; or quinolinyl substituted with one or two substituents selected from;hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl;
Ar is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, C1-4alkyl or C1-4alkyloxy;
Het is furanyl; furanyl substituted with C1-4alkyl, C1-4alkyloxy or hydroxyC1-4alkyl; oxazolyl; oxazolyl substituted with C1-4alkyl or C1-4alkyloxy; or quinolinyl; for the manufacture of a medicine for improving the bioavailability of a second pharmaceutical agent which is co-administered orally to a warm-blooded animal.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo, C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl includes C1-4alkyl and the higher homologues thereof having from 5 to 6 carbon atoms such as, for example, pentyl, hexyl, 3-methylbutyl, 2-methylpentyl and the like; C1-12alkyl includes C1-6alkyl and the higher homologues thereof having from 7 to 12 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl and the like; C1-4alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediol, 1,3-propanediyl, 1,4-butanediyl and the like; C1-5alkanediyl includes C1-4alkanediyl and the higher homologues thereof having 5 carbon atoms such as, for example, 1,5-pentanediyl and the like; C1-6alkanediyl includes C1-5alkanediyl and the higher homologues thereof having 6 carbon atoms such as, for example, 1,6-hexanediyl and the like; C2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C2-6alkenediyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethanediol, 2-propenediyl, 3-butenediyl, 2-pentenediyl, 3-pentenediyl, 3-methyl-2-butenediyl, and the like; halo-C1-4alkyl is defined as mono- or polyhalosubstituted C1-4alkyl; C1-6alkanediyl-oxy-C1-6alkanediyl defines bivalent radicals of formula such as, for example, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(CH2CH3)xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94 and the like.
Whenever the bivalent radical A1 is defined as a C1-6alkanediylcarbonyl or C1-6alkanediyloxy, preferably the C1-6alkanediyl part of said radicals is connected to the nitrogen atom of the piperidine ring.
Pyridinyl and quinolinyl in the definition of Q are preferably connected to A2 by a carbon atom.
Whenever Z is defined as Z2, the xe2x80x94CH2xe2x80x94 moiety of said bivalent radical is preferably connected to the nitrogen of the imidazole ring.
Wherever R1 or R10 is defined as imidazolyl, thiazolyl or oxazolyl, said substituents are preferably connected by a carbon atom to the rest of the molecule.
The compounds where Z is xe2x80x94CH2xe2x80x94 and the optional bond is present are excluded by proviso because the tricyclic moiety in such compounds spontaneously aromatizes, thereby losing its multidrug resistance modulating properties.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base addition salt forms which the compounds of formula (I) are able to form. Examples of such base addition salt forms are, for example, the sodium, potassium, calcium salts, and also the salts with pharmaceutically. acceptable amines such as, for example, ammonia, alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e.g. arginine, lysine.
Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The term stereochemically isomeric forms as used hereinbefore defines the possible different isomeric as well as conformational forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some compounds of the present invention may exist in different tautomeric forms and all such tautomeric forms are intended to be included within the scope of the present invention. For instance, compounds of formula (I) wherein Q is pyridinyl or quinolinyl substituted with hydroxy, may exist in their corresponding tautomeric form.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein the piperidine-nitrogen is N-oxidized.
A first group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
a) xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula (b-2), (b-3) or (b4); or
b) Z is Z1 wherein Z1 is a bivalent radical of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94; or
c) xe2x80x94A1xe2x80x94 is C1-6alkanediyl, C1-6alkanediyloxy, carbonyl, C1-6alkanediyloxy substituted with hydroxy, or C1-6alkanediyl substituted with hydroxy; in particular xe2x80x94A1xe2x80x94 is C1-6alkanediyl; or
d) xe2x80x94A2xe2x80x94 is a direct bond or C1-6alkanediyl; in particular xe2x80x94A2xe2x80x94 is C1-6alkanediyl;
e) Q is phenyl, naphthalenyl, pyridinyl or quinolinyl, and optionally said Q is substituted with halo, C1-6alkyl or C1-6alkyloxy;
f) R1 is hydrogen, halo, formyl, C1-4alkyl substituted with hydroxy, or a radical of formula (a-1) wherein X is a direct bond or C1-4alkanediyl and R5 is hydrogen, C1-12alkyl, Ar or C1-6alkyl substituted with Het;
g) R2 is hydrogen, halo, C1-4alkyl, formyl, hydroxyC1-4alkyl or C1-4alkyloxycarbonyl;
h) R3 is hydrogen;
i) R4 is hydrogen, halo, C1-6alkyl or C1-6alkyloxy.
A second group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
a) xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula (b-2), (b-3) or (b4); or
b) Z is Z2 wherein Z2 is a bivalent radical of formula xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94; or
c) xe2x80x94A1xe2x80x94 is C1-6alkanediyl, C1-6alkanediyloxy, carbonyl, C1-6alkanediyloxy substituted with hydroxyl or C1-6alkanediyl substituted with hydroxy; in particular xe2x80x94A1xe2x80x94 is C1-6alkanediyl; or
d) xe2x80x94A2xe2x80x94 is a direct bond or C1-6alkanediyl; in particular xe2x80x94A2xe2x80x94 is C1-6alkanediyl;
e) Q is phenyl, naphthalenyl, pyridinyl or quinolinyl, and optionally said Q is substituted with halo, C1-6alkyl or C1-6alkyloxy;
f) R1 is hydrogen, halo, formyl, C1-4alkyl substituted with hydroxy, or a radical of formula (a-1) wherein X is a direct bond or C1-4alkanediyl and R5 is hydrogen, C1-12alkyl, Ar or C1-6alkyl substituted with Het;
g) R2 is hydrogen, halo, C1-4alkyl, formyl, hydroxyC1-4alkyl or C1-4alkyloxycarbonyl;
h) R3 is hydrogen;
i) R4 is hydrogen, halo, C1-6alkyl or C1-6alkyloxy.
A particular group of compounds are those compounds of formula (I) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula (b-2), (b-3) or (b4) wherein R8 is hydrogen or halo; Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94; xe2x80x94A1xe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94 CH2xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94; A2xe2x80x94 is xe2x80x94CH2xe2x80x94 and the dotted line is a bond.
Another particular group of compounds are those compounds of formula (I) wherein Q is 2-quinolinyl, 1-naphthalenyl, 2-naphthalenyl, phenyl or 2-pyridinyl and said Q is optionally substituted with C1-4alkyl, halo, haloC1-4alkyl or C1-4alkyloxy.
A further particular group are those compounds of formula (I) wherein Q is 2-quinolinyl, 1-naphthalenyl, 2-naphthalenyl, 6-methyl-2quinolinyl, 6-chloro-2-pyridinyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 3,5-difluorophenyl, or 3,5-bis(trifluoromethyl)phenyl.
Preferred compounds are those compounds of formula (I) wherein Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94; xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94A1xe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94CH2CH2xe2x80x94; xe2x80x94A2xe2x80x94 is xe2x80x94CH2xe2x80x94; R1 is hydrogen, halo, formyl or a radical of formula (a-1) wherein X is a direct bond and R5 is hydrogen, C1-12alkyl, Ar or C1-6alkyl substituted with Het; R2 is hydrogen, C1-4alkyl, formyl or C1-4alkyloxycarbonyl; R3 is hydrogen; R4 is hydrogen or C1-4alkyloxy and the dotted line is a bond.
Most preferred compounds of formula (I) are
methyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;
dimethyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-2,3-dicarboxylate;
ethyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;
methyl 11-[1-[[3,5-dimethoxy-4-(2-quinolinylmethoxy)phenyl]methyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;
methyl 6,11-dihydro-11-[1-[3-[4-(2-quinolinylmethoxy)phenyl]propyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;
methyl 6,11-dihydro-11-[1-[2-[4-(2-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;
methyl 6,11-dihydro-11-[1-[2-[4-(phenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; and
methyl 6,11-dihydro-11-[1-[2-[4-(1-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;
the stereoisomeric forms and the pharmaceutically acceptable addition salts thereof.
In the following paragraphs there are described different ways of preparing the compounds of formula (I). In order to simplify the structural formulae of the compounds of formula (I) and the intermediates intervening in their preparation, the fused imidazole moiety will be represented by the symbol T hereinafter. 
The compounds of the present invention can generally be prepared by N-alkylating an intermediate of formula (III) wherein W is an appropriate leaving group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy, with an intermediate of formula (II). The reaction can be performed in a reaction-inert solvent such as, for example, ethanol, dichloromethane, methyl isobutylketone or N,N-dimethylformamide, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature. 
Compounds of formula (I) may also be prepared by O-alkylating an intermediate of formula (V) with an intermediate of formula (IV), wherein W1 is an appropriate leaving group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy. The reaction can be performed in a reaction-inert solvent such as, for example, N,N-dimethylformamide, and in the presence of a suitable base such as, for example, sodium hydride, preferably at a temperature ranging between room temperature and reflux temperature. 
Compounds of formula (I) wherein xe2x80x94A1xe2x80x2xe2x80x94 represents C1-6alkanediyl, C1-6alkanediyloxy, C1-6alkanediyloxyC1-6alkanediyl, said compounds being represented by formula (I-i), may be prepared by reductive N-alkylation of an intermediate of formula (III) with an intermediate of formula (XIX). In said intermediate (XIX), xe2x80x94A1xe2x80x3xe2x80x94 represents a direct bond, C1-5alkanediyl, C1-5alkanediyloxy or a C1-6alkanediyl-oxyC1-5alkanediyl moiety whereby the formyl group is bonded on the C1-5alkanediyl part. 
Said reductive N-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of a reducing agent such as, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. To enhance the rate of the reaction, the temperature may be elevated in a range between room temperature and the reflux temperature of the reaction mixture.
In the following paragraphs there are described different ways of converting compounds of formula (I) into each other following art-known functional group transformation procedures. In order to simplify the structural formulae of the compounds of formula (I), the substituted piperidine moiety will be represented by the symbol M hereinafter. 
For instance, compounds of formula (I) wherein R1 is C1-4alkyl substituted with hydroxy, said compounds being represented by formula (I-a), may be converted in the corresponding compounds of formula (I) wherein R1 is C1-4alkylcarbonyloxyC1-4alkyl, said compounds being represented by formula (I-b), according to art-known esterification methods such as, e.g. treatment with an acyl halide in the presence of a base to pick up the acid liberated during the reaction. 
Also, compounds of formula (I-a) wherein R1 is CH2OH, said compounds being represented by formula (I-a-1), may be converted in the corresponding compounds of formula (I) wherein R1 is CHO, said compounds being represented by formula (I-c), by oxidation with a suitable reagent such as, e.g. manganese(IV)oxide. 
Further, compounds of formula (I) wherein R1 contains a carboxyl group, said compounds being represented by formula (I-d), may be converted in the corresponding esters by art-known methods such as, e.g. treatment with an alcohol in the presence of an acid or base. 
Conversely, compounds of formula (I-e) may be hydrolyzed into compounds of formula (I-d), in the presence of an acid or a base.
The compounds of formula (I-c) may be converted into compounds of formula (I) wherein R1 is a methoxycarbonylmethyl, said compounds being represented by formula (I-f), by treatment with methyl methylthiomethyl sulfoxide in the presence of benzyltrimethyl ammonium hydroxide in a reaction-inert solvent, e.g. tetrahydrofuran. 
Also, compounds of formula (I-c) may be converted into compounds of formula (I-e) wherein X is a direct bond, said compounds being represented by formula (I-e-1), by treatment with an; alcohol, such as, e.g. methanol or ethanol, in the presence of acetic acid, MnO2 and NaCN. 
Compounds of formula (I) wherein Z2 represents xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94, said compounds being represented by formula (I-g), can be converted in the corresponding alcohols by art-known reduction procedures such as, e.g. treatment with sodiumborohydride in a suitable solvent, e.g. methanol. 
The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art. For example, a number of intermediates of formula (III),especially those wherein Z is Z2, are known compounds which may be prepared according to art-known methodologies described in EP-0,518,435-A, EP-0,518,434-A and WO-95/02600.
In the following paragraphs there are described several methods of prepraring the intermediates employed in the foregoing preparations.
The intermediates of formula (II) may be prepared by O-alkylating the aromatic hydroxyl group of intermediate (VI) with an intermediate of formula (IV), wherein W1 is a suitable leaving group such as, e.g. halo, methanesulfonyloxy or benzenesulfonyl-oxy, and subsequent conversion of the hydroxy group of intermediate (VII) into leaving group W, e.g. by treating intermediate (VII) with methanesulfonyloxy chloride or a halogenating reagent such as, e.g. POCl3. 
Said O-alkylation reaction can conveniently be carried out by mixing the reactants in a reaction-inert solvent such as, for example, methanol or N,N-dimethylformamide, and in the presence of an appropriate base such as, e.g. sodium carbonate or sodium hydrogen carbonate, preferably at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.
Also, intermediates of formula (II) wherein xe2x80x94A1xe2x80x94 is C1-6alkanediyloxy, said intermediates being represented by compounds of formula (II-a), may be prepared by reacting an intermediate of formula (VIII) with an intermediate of formula (IX) in the presence of an appropriate base such as, e.g. potassium carbonate, and optionally in the presence of a reaction-inert solvent such as, for example, N,N-dimethylformamide, acetonitrile or tetrahydrofuran. Subsequent conversion of the hydroxy group into a leaving group W, e.g. by treatment with methanesulfonyloxy chloride or a halogenating reagent such as, e.g. POCl3, yields intermediates of formula (II-a). It may be advantageous to conduct said O-alkylation reaction at a temperature ranging between 
In an embodiment, the present invention also provides for novel compounds of formula (II), represented by compounds of formula (II-b) wherein radical xe2x80x94A1xe2x80x2xe2x80x94 represents C1-6alkanediyl, C1-6alkanediyloxy or C1-6alkanediyloxyC1-6alkanediyl and Q1 represents all substituents Q other than unsubstituted phenyl. 
Intermediates of formula (V) wherein xe2x80x94A1xe2x80x2xe2x80x94 represents C1-6alkanediyl, C1-6alkanediyloxy, C1-6alkanediyloxyC1-6alkanediyl, said intermediates being represented by formula (V-a), may be prepared by reductive N-alkylation of an intermediate of formula (III) with an intermediate of formula (X). Optionally, intermediate (X) has a protected hydroxyl group which can be deprotected using art-known methods subsequent to the reductive N-alkylation. In said intermediate (X), xe2x80x94A1xe2x80x3xe2x80x94 represents a direct bond, C1-5alkanediyl, C1-5alkanediyloxy or C1-6alkanediyl-oxyC1-5alkanediyl whereby the formyl group is bonded on the C1-5alkanediyl part. Said reductive N alkylation may be performed according to the hereinabove described procedure. 
Intermediates of formula (III-a), defined as intermediates of formula (III) wherein Z is Z1, may be prepared according to scheme I. 
In scheme I, an intermediate of formula (XII) can be cyclized in an analogous way as an intermediate of formula (XI), giving an alcohol of formula (XIII) which can be oxidized following art-known oxidation methods into a ketone of formula (XIV). An intermediate of formula (XVI) can be prepared by addition of a Grignard reagent (XV), wherein PG is a suitable protecting group, e.g. benzyl, to a ketone of formula (XIV) in a reaction-inert solvent, e.g. tetrahydrofuran. An intermediate of formula (III-a) can be prepared by dehydration of an intermediate (XVI) subsequently with catalytic hydrogenation of an intermediate (XVII). Said dehydration reaction can conveniently be conducted employing conventional dehydrating reagents, e.g. sulfuric acid, following art-known methodologies. Said catalytic hydrogenation reaction can be conducted following art-known procedures, e.g. stirring in a reaction-inert solvent, e.g. methanol, in the presence of a suitable catalyst, e.g. palladium-on-carbon and in the presence of hydrogen, optionally the temperature may be elevated in a range between room temperature and the reflux temperature of the reaction mixture and, if desired, the pressure of the hydrogen gas may be raised.
Further, intermediates of formula (III-a) wherein R1 is halo, said intermediates being represented by formula (III-a-1), can be prepared by halogenating intermediates of formula (XVIII) wherein PG is a protective group such as, e.g. C1-6alkyl, and subsequent depiotection. For instance, when PG is C1-6alkyl, PG may be removed by a carbonylation reaction with a C1-4alkylchloroformate and subsequent hydrolysis with a base. 
Said halogenation reaction can conveniently be conducted by treating intermediates (XVIII) with a halogenating reagent such as, for example, N-chlorosuccinimide or N-bromosuccinirride, in a reaction-inert solvent such as, e.g. dichloromethane, optionally in the presence of an initiator such as, e.g. dibenzoyl peroxide.
Also, the intermediates of formula (III) wherein Z is Z1 and the dotted line is not a bond, said intermediates being represented by compounds of formula (III-b), can generally be prepared by cyclizing an intermediate of formula (XI). 
Said cyclization reaction is conveniently conducted by treating an intermediate of formula (XI) with an appropriate acid, yielding an intermediate of formula (III-a). Appropriate acids are, for example, methanesulfonic acid or trifluoromethanesulfonic acid. It should be noted that only those intermediates of formula (III-a) wherein R1 and R2 are stable under the given reaction conditions can be prepared according to the above reaction procedure.
Compounds of formula (I) and some of the intermediates may have one or more stereogenic centers in their structure, present in a R or a S configuration.
The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and stereoisomeric forms thereof have valuable pharmacological properties in that they inhibit transport of a chemotherapeutic agent through a membrane by a inembrane-associated transporter, especially the membrane-associated transporter P-glycoprotein, and thereby inhibit or reverse the effects of multidrug resistance, as can be evidenced by the results obtained in the MDR in vitro test (Example C-1) and the MDR in vivo test (Example C-2).
In view of their MDR inhibiting properties, the compounds of formula (I) are usable for the manufacture of a medicine to improve the oral bioavailability of pharmaceutical agents that are poorly absorbed or not absorbed at all from the gastrointestinal tract or gut by pre-administering and/or simultaneously administering to a warm-blooded animal by the oral route a compound of formula (I). As demonstrated in Example C-3 the compounds of formula (I) are able to improve oral bioavailability.
The improved oral bioavailability of a second pharmaceutical agent when co-administered with a compound of formula (I) can be determined by measuring the total systemic concentration of said pharmaceutical agent over time after co-administration of said pharmaceutical agent and a compound of formula (I) and after administration of only the pharmaceutical agent. The increase in drug bioavailability is defined as an increase in the Area Under the Curve (AUC). AUC is the integrated measure of systemic drug concentrations over time in units of mass-time/volume. The AUC from time zero (the time of dosing) to time infinity (when no drug remains in the body) following the administration of a drug dose is a measure of the exposure of the test subject, i.e. an animal or a human patient, to the drug.
Co-administration of a compound of formula (I) and a second pharmaceutical agent that is poorly absorbed or not absorbed at all from the gastrointestinal tract comprehends administration substantially simultaneously with said pharmaceutical agent (either less than 30 minutes before, less than 30 minutes after or together), from about 30 minutes to about 24 hours before the administration of the pharmaceutical agent, or both, i.e. with one or more doses of the same compound of formula (I) given at least 30 minutes before and one dose given simultaneously with (either together with or immediately before or after) the pharmaceutical agent. In general, xe2x80x9cco-administrationxe2x80x9d means the first pharmaceutical compound of formula (I) and the second pharmaceutical agent are present in the gut lumen and/or membranes during at least partially overlapping times. Additionally, xe2x80x9cco-administrationxe2x80x9d comprehends administering more than one dose of said pharmaceutical agent within 24 hours after a dose of the compound of formula (I), in other words, the compound of formula (I) need not be administered again before or with every administration of said pharmaceutical agent, but may be administered intermittently during the course of treatment.
Suitable pharmaceutical agents for use in the combinations defined above include are, e.g., anti-neoplastic agents such as, e.g. paclitaxel (Taxol(copyright)), docetaxel (Taxotere(copyright)), other related taxanes, adriamycine, cladribine, cisplatin, cyclophosphamide, dactinomycin, daunorubicin, doxorubicin, etoposide, finasteride, 5-fluorouracil, irinotecan, leucovorin, mitomycin, mitoxantrone, tamoxifen, topotecan, trimetrexate, vincristine, vinblastine and the like.
Other suitable pharmaceutical agents can be compounds from classes, such as, but not limited to, aminoacridines, aminoquinolines, anilides, anthracycline antibiotics, antiestrogens, benzofurans, benzhydryl compounds, benzazepines, cannabioids, cephalosporines, colchicine, cyclic peptides, dibenzazepines, epipodophyllotoxins, flavonoids, flavones, imidazoles, isoquinolines, macrolides, opioids, phenylakylamines, phenothiazines, piperazines, piperidines, pyrrololidines, quinazolines, quinolines, quinones, rauwolfia alkaloids, retinoids, salicylates, sorbitans, steroids, triazoles, unsaturated fatty acids and vinca alkaloids.
Diseases, disorders or conditions wherein the above-mentioned anti-neoplastic agents are used are, for example, neoplastic diseases caused by the growth of neoplasms (or tumors) such as, for example, haematological tumors (leukemias, lymphomas), renal carcinoma, melanoma, ovarian cancer, breast cancer, lung cancer, head and neck carcinomas, hepatocellular carcinoma, liver metastases, genito-urinary and gastrointestinal tract cancers and Kaposi""s sarcoma.
The first pharmaceutical compound of formula (I) is used in combination with a second pharmaceutical agent that is poorly absorbed or not absorbed at all from the gastrointestinal tract. The invention thus provides a combination containing a composition as defined herein comprising a first pharmaceutical compound of formula (I), together with a composition as defined herein comprising a second pharmaceutical agent, in particular an anti-neoplastic agent. The combination may be orally administered separately, simultaneously or consecutively, or the combination may also be presented in the form of one pharmaceutical formulation. Thus, a pharmaceutical product comprising (a) a first pharmaceutical compound of formula (I) and (b) a second pharmaceutical agent that is poorly absorbed or not absorbed at all from the gastrointestinal tract, as a combined preparation for simultaneous, separate or sequential use in the therapeutic or prophylactic treatment of warm-blooded animals. Such a product may comprise a kit comprising a container containing a pharmaceutical composition of a compound of formula (I), and another container comprising a pharmaceutical composition of the pharmaceutical agent that is poorly absorbed or not absorbed at all from the gastrointestinal tract. The product with separate compositions of the two active ingredients has the advantage that appropriate amounts of each component, and timing and sequence of administration can be selected in function of the patient.
When compounds of formula (I) are used in combination with a second pharmaceutical agent that is poorly absorbed or not absorbed at all from the gastrointestinal tract, the dose of said pharmaceutical agent may vary from the dose when used alone.
For oral administration, when compounds of formula (I) are co-administered with a second pharmaceutical agent the dose of the latter may be the same or more commonly, lower, than the dose employed when the pharmaceutical agent is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
Pharmaceutical ,agents that are so poorly absorbed from the gastrointestinal tract that no oral dosage form is available may become suitable for oral administration when used in combination with a compound of formula (I).
In view of the above uses of the compounds of formula (I), it follows that the present invention also provides a method of improving the bioavailability upon oral co-administration to a warm-blooded animal, in particular to a human, of a second pharmaceutical agent. Said method comprises the oral co-administration to said warm-blooded animal of a second pharmaceutical agent that is poorly or not absorbed at all from the gastrointestinal tract and a compound of formula (I). Also provided is a method wherein the compound of formula (I) and the pharmaceutical agent are each administered in a separate oral dosage form or in a combination oral dosage form.
For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for administration purporses. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more; suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The compositions may advantageously be presented in discrete dose units, especially in unit dosage forms. A convenient unit dose formulation contains the active ingredient in an amount of from 0.1 to 1000 mg, and in particular from 1 to 200 mg. The amount of a compound of formula (I) required as daily dose in treatment will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition being treated and the age, weight and condition of the patient and will ultimately be at the discretion of the attendant physician. In general, however, a suitable daily dose will be in the range of from about 0.1 to about 5000 mg per day, in particular from about 1 to 1000 mg per day, more particular from about 10 to 500 mg per day. Other daily dosing schemes are administration of twice-daily doses of 200 or 300 mg. A suitable daily dose for use in prophylaxis will generally be in the same range.